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The taming of the flu

By Philip Cohen

FOR the first time, biologists have pieced together a flu virus from scratch
by sneaking all the virus’s genes into cells. Experts say their “designer flus”
may help create powerful new vaccines and even deliver genes to treat other
diseases.

Three times this century, flu strains have emerged with lethal force
worldwide. The most famous of these was the Spanish flu pandemic of 1918, which
contributed to more than 20 million deaths. And every winter, lesser strains of
the flu emerge to threaten the lives of older people and those whose immune
systems have been weakened by disease.

Most current vaccines against flu consist of chemically inactivated virus
which primes the immune system against viral proteins. But these vaccines aren’t
always effective. And deleting the troublesome genes from the virus to make a
live vaccine has turned out to be very difficult.

The problem is that the flu virus is unusually complex. It has eight separate
pieces of RNA and many different proteins. When virologists try to engineer a
safe version with mutated genes, they can only make it replicate in cells by
adding “helper” strains of intact flu virus to provide the missing pieces. In
the process, the RNA pieces get mixed up and diluted by the helper, so isolating
viruses with many mutated genes has been extremely difficult.

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But now Yoshihiro Kawaoka of the University of Wisconsin in Madison and his
colleagues have done what few people thought possible: they have assembled flu
viruses by introducing all the pieces of the virus into cells on DNA circles
called plasmids. The cells use these fragments to make the RNAs and proteins of
an engineered virus without a helper.

The big challenge was the sheer number of plasmids. Cells are sometimes
reluctant to accept just a few of them, and Kawaoka was going to attempt a total
of 17. “This is the type of idea you don’t say too loudly,” he says. “You are
afraid that someone might laugh.”

But in the end the idea worked brilliantly, producing up to 50 million
viruses for each millilitre of cell culture. The researchers also showed they
could use the system to quickly replicate and harvest a mutant form of the virus
that had previously been impossible to mass-produce (Proceedings of the
National Academy of Sciences, vol 96, p 9345).

“It’s astonishingly efficient,” says virologist Robert Lamb of Northwestern
University. “Like many researchers, I’m eager to get my hands on Kawaoka’s
reagents.” Lamb suggests it should be possible to create the building blocks of
a highly weakened influenza strain to use as a “master flu vaccine”—a
library of plasmids that can be added to when a new strain of flu comes
along.

Kawaoka says his team is already working on this idea. Now that copious
amounts of mutant flu are available, he adds, it could be used to present
proteins from other pathogens to the immune system, making it a multipurpose
vaccine. Perhaps most intriguingly, he thinks the tamed virus—which is
still highly infectious—could infect cells and deliver genes to treat
disease. “We already know so much about influenza,” he says. “With this
technology, we are ready to move in many different directions.”